A responsive yet persistently recurrent GBM with PNET features

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CASE SUMMARY

A 49-year-old male presented to his primary provider with a 6-month
history of unilateral resting tremor and tingling facial sensations.
Cranial MRI revealed a 6 × 3.1-cm hemorrhagic lesion in the right
temporal lobe (Figure 1). The patient underwent gross total resection
(GTR) revealing tissue consistent with glioblastoma multiforme (GBM).
While the large lesion was in close proximity to multiple meningeal
structures, neither imaging nor intraoperative assessments strongly
indicated leptomeningeal disease. However, neuroblastic foci positive
for synaptophysin with a Ki-67 proliferation index approaching 100% were
also identified. As a result, the diagnosis of GBM with primitive
neuroendocrine tumor (PNET) features was made. The patient underwent
adjuvant volumetric-modulated arc radiation therapy (VMAT) at 59.4 Gy in
1.8 Gy fractions followed by a stereotactic radiosurgery (SRS) boost at
17 Gy to the 50% iso-dose line to an area of residual enhancement.
Adjuvant temozolamide was also provided.

Imaging performed 1 month after completion of the patient’s initial
course of treatment showed dural-based lesions in bilateral frontal
lobes that were also hypermetabolic on positron emission tomography
(PET) (Figure 2). Hence, approximately 8 months from initial surgical
resection, the patient underwent a left-sided craniotomy and GTR of the
largest lesion, which confirmed an out-of-field, contralateral
recurrence of his GBM with PNET features. Another round of adjuvant
radiation via VMAT at 55.8 Gy with concurrent temozolamide was
initiated, targeting the resection cavity and the right-sided lesion.

The patient retained stable functional capacity with no new
neurological symptoms or complaints. However, follow-up imaging showed a
local recurrence in the right temporal lobe where the initial resection
had been performed 12 months earlier (Figure 3A). The patient started a
regimen of etoposide and vincristine, but after 1 cycle, he developed
seropurulent drainage from his craniotomy site with projectile vomiting,
neck stiffness and low back pain. He was diagnosed with acute
meningitis requiring craniectomy with bone washing and intravenous
antibiotic therapy. After recovering, he began a regimen of
procarbazine, lomustine, and vincristine (PCV) with bevacizumab.
Subsequently, resolution of the previously noted contrast enhancement
had resolved, and all therapies were
discontinued.

Nevertheless, in the follow-up 24 months after his initial
craniotomy, imaging revealed another local recurrence with contrast
enhancement in the temporal lobe (Figure 3B). With minimal morbidity and
stable performance status, the patient wished to pursue aggressive
treatment, so the recurrent area was given a third round of VMAT to 39.6
Gy with concurrent temozolamide and bevacizumab, followed by adjuvant
etoposide, carboplatin and bevacizumab.

Two months following therapy, the patient complained of weakness,
somnolence, weight loss and low back pain. Brain imaging remained
stable, but spinal imaging demonstrated extensive leptomeningeal
disease. Although a palliative course of radiation was initiated, the
patient succumbed to his disease shortly thereafter, approximately 28
months following initial diagnosis and resection.

IMAGING FINDINGS

Initial diagnostic MRIs showed a heterogeneously enhancing mass in
the right temporal lobe with peritumoral edema, midline shift, and uncal
herniation. The T1 phase of this exam is provided in Figure 1.
Functional MRI also revealed language localization of the left, and the
mass to be separated from the motor strip. The patient’s initial
recurrences in bilateral frontal lobes were also enhancing, yet more
homogenously, and were closely approximated to the cerebral meninges.
This exam, as well as a PET/CT of the brain showing the increased
metabolic activity at these sites, is shown in Figure 2. After treatment
for these lesions, follow-up imaging showed a local recurrence at the
initial site following a second round of radiation and temozolamide
therapy (Figure 3, left), followed by persistent disease after an
additional 12 months of chemotherapy and a lengthy hospitalization for
meningitis (Figure 3, right). And finally, the patient’s disease
eventually spread to his sacral spine via leptomeningeal dissemination,
which was seen on lumbosacral MRI exams as “sugar-coating” confluent
lesions of the cauda equina and thickening of the surrounding meninges
and dura.

DIAGNOSIS

Multipally recurrent glioblastoma multiforme (GBM) of the right
temporal lobe with primitive neuroendocrine tumor (PNET) features and
leptomeningeal dissemination.

DISCUSSION

Currently, standard treatment for GBM includes local radiation
therapy and temozolamide. Although GBM has classically been considered a
purely astrocytic tumor, lesions with mesenchymal and epithelial
constituents are increasingly being described.GBM with PNET
components are thought to represent approximately 0.5% of GBM cases, and
arise from the development of PNET-like foci within pre-existing
gliomas.In contrast to conventional GBM, PNETs typically
have a histology similar to medulloblastoma and are often managed with
combined craniospinal radiation and platinum-based chemotherapy.

The majority of GBM tumors are resistant to therapy, and mean survival is approximately 15-17 months.Although
the prognosis for PNET patients is also fairly poor, the response rate
to therapy is more marked, with an estimated 4-year survival rate of
38%. An established clinical feature of PNETs is a high risk for
metastatic spread into the cerebrospinal fluid (CSF).Although
the clinical data is sparse, recent studies have suggested that
patients with GBM-PNETs are also at increased risk for CSF
dissemination.In a recent multi-institutional series of 53
patients with GBM-PNETs, Perry et al reported leptomeningeal metastasis
in up to 40% of patients. This frequency is in sharp contrast to the
approximate 1% CSF spread rate seen in adult patients with conventional
GBM. Three of the patients in the study with leptomeningeal spread were
eventually switched from temozolamide to cisplatin, with moderate
responses in each.3

Our case of GBM-PNET was treated with 3 successive rounds of combined
radiation and temozolamide therapy, including an SRS boost, with
salvage PVC and bevacizumab therapy. This approach resulted in modest
local responses and control. This patient, whose age, performance
status, and therapy would suggest a median overall survival of 16-21
months, survived 28 months from initial resection.9 The
patient did experience a prolonged hospitalization for treatment of
acute meningitis, but his neurocognitive and functional deficits
remained mild and transient until late in his progression. Other than
fatigue noted around the late and subsequent weeks of his radiation
treatments, which was milder than expected, this patient experienced
very minimal neurocognitive decline until his last few weeks of life,
and, outside of his infection-related hospitalization, only rarely
reported episodes of headache, nausea, or other forms of acute toxicity.
Nevertheless, all therapies ultimately failed to control
leptomeningeal spread. Although this is insufficient data to provide
conclusive therapeutic recommendations, given the differences in
metastatic potential between GBM and PNET tumors, it can be speculated
that patients with histologically confirmed GBM with PNET features may
benefit from craniospinal irradiation, a commonly used therapy for
treating PNETs and medulloblastoma, or the early introduction of
platinum-based chemotherapy.3,10

Our experience is consistent with the scant literature and clinical
guidelines concerning management of GBM-PNETs. Conventional GBM tumors
rarely undergo metastatic spread, and standard management is directed
toward the control of local disease. As identifying PNET components in
GBMs may have prognostic and treatment ramifications, the method of
tumor sampling during biopsy may influence management considerations.
Tumors are spatially heterogeneous; therefore, determining both the
distribution and functionality of PNET foci within primary lesions is
likely help predict clinical behavior. One study suggests that the
diffusion coefficient on MR imaging may help distinguish astrocytic and
ectodermal tumor components, potentially guiding biopsies.

CONCLUSION

GBM-PNET tumors are aggressive neoplasms of mixed embryologic origin
that demonstrate high rates of local recurrence and dissemination into
the CSF. Our patient with GBM-PNET was treated with multiple courses of
surgery, radiation and chemotherapy. Therapy provided favorable local
responses with an overall survival of 28 months after extensive therapy
without debilitating morbidity. The patient tolerated his multiple
courses of radiation therapy with minimal complaints of acute toxicity,
and, unlike many high-grade glioma patients who do not survive long
enough to experience late toxicities, he experienced late toxicity only
in the last weeks of his survival. The patient did, despite all
aggressive therapy, eventually manifest leptomeningeal spread, which led
to a rapid symptomatic decline and death from his disease. This case
suggests that aggressive therapies may be utilized in attempts to
prolong survival with acceptable toxicity during this period in select
patients with favorable performance status. And furthermore, patients
with diagnoses of GBM-PNET may benefit from advanced techniques of
diagnostic imaging and pathologic analysis, as well as craniospinal
irradiation and early platinum-based chemotherapy due to the propensity
for CSF
dissemination.